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The same man was never attacked twice

Thucydides describing the plague of

Athens in 430 B.C.

of the many aged people still living on the

Faroes who had had measles in 1781, not

one was attacked a second time

Panum investigating the measles outbreak

on the Faroe Islands in 1846.

The immune system has evolved to defend us against infectious diseases and one of its cardinal features is its ability to blunt the severity of a second infection with the same pathogen. This remarkable phenomenon was first recorded in 430 B.C. by the Greek historian Thucydides and for centuries mankind has known that certain diseases are seldom suffered a second time. In fact, it was this observation that gave birth to the term ‘immunity’; the old Roman word ‘immunitas’ meaning protection from taxation was adopted to describe this protection from disease.

More importantly, the discipline of vaccinology originated from this principle and immunological memory forms the underlying basis for vaccination. The earliest attempts to induce protective immunity were made in Asia around 1500 AD, when dried pox material from smallpox patients was inoculated into healthy people. This process, called variolation, protected individuals from smallpox. Lady Montague Wortley, an Englishwoman, introduced this procedure to the West, but this approach did not gain popularity and was discontinued because the degree of morbidity associated with variolation was simply too variable and too high to be acceptable. The major breakthrough came with the studies of Edward Jenner in 1796. Jenner made the astute observation that milkmaids who were exposed to cowpox were spared the ravages of smallpox and reasoned that inoculation of cowpox pustular material might prevent smallpox. He was right, of course, and the rest, as they say, is history – Jenner's vaccine was highly effective and eventually led to the eradication of smallpox.

How does the immune system remember, sometimes for a lifetime, the identity of a pathogen? What is the cellular and molecular basis of this immunological memory? How is this memory maintained? Why is protective immunity long-lived for some infections but short-lived for others? When immunity fails, how is this explained? These questions have fascinated immunologists for many years and the answers to these central questions are now beginning to emerge. We have been most fortunate to bring together in this volume articles by investigators who are the world's leaders in this field and whose work has provided most of our current understanding of T and B cell memory. In the true spirit of Immunological Reviews, they have expressed their opinions not only with scholarship but also with passion.

We start the volume with five articles on memory CD4 T cells – the central orchestrators of the immune system that are critical for generating effective humoral immunity as well as CD8 T cell memory. Swain and colleagues examine the roles of antigen and inflammation in differentiation of memory CD4 T cells. They emphasize the heterogeneity that is seen among effector and memory CD4 T cells to influenza virus and discuss the possibility of developing T cell based vaccines against influenza. Dooms and Abbas discuss how cytokines and costimulatory molecules regulate memory CD4 T cell differentiation and maintenance. In particular, they highlight the importance of cytokines IL-2 and IL-7 and the costimulator CD28 in the programming and survival of memory CD4 T cells. Stockinger et al. take on the important topic of CD4 T cell homeostasis and address how this impacts on heterogeneity and plasticity of the memory T cell phenotype and its function. Marrack, Kappler and colleagues point out that not all memory CD4 T cells are long-lived and discuss critical issues about the life-span of naive versus memory cells. They also engage in a lively debate about the semantics of “memory”. This issue is also discussed in several of the articles on CD8 T cell memory (see below). The final article on CD4 memory T cells by the Seder group discusses the functional importance of the different cytokine producing subsets and examines their role in protective immunity. It then addresses the important question of how we can use this information to design more effective vaccines for infections requiring Th1 responses.

We have a large collection of articles dealing with memory CD8 T cells – the professional killers of the immune system whose mission is to seek and destroy. The advent of MHC class I tetramer technology about a decade ago broke this field wide open – for the first time immunologists could actually see their favorite memory cells, track their movement and function in vivo, and isolate pure populations of antigen specific cells. This resulted in rapid advances in our understanding of memory CD8 T cells and also attracted many new investigators into this area of research. In fact, there are so many groups currently working on CD8 T cell memory that we were forced to leave out some of the outstanding junior investigators in this field. Our apologies to our young colleagues but they can take solace in the fact that the future belongs to them and they will almost certainly occupy center stage when Immunological Reviews does its next volume on memory.

Several of the articles deal with differentiation of memory CD8 T cells. Harty and Badovinac present evidence for a programming model for CD8 T cell memory induction. They point out the potential plasticity of memory cells but emphasize that manipulating this is most effective if stimuli are provided very early in the induction process. Mescher et al. also deal with programming events for the induction of effector and memory CD8 T cells. They propose a 3 signal model wherein the signals are provided by dendritic cells that in turn are influenced by CD4 T cells. The third signals are mainly cytokines such as IL-12 and IFN alpha. Leo Lefrancois emphasizes that the useful function of memory cells depends very much on their location. He suggests the existence of multiple memory T cell pools, likely with different molecular signatures, and explains how to influence memory cells to locate in various tissues. Fearon and colleagues examine the relationship of effector T cells to self-renewing central memory cells. They advocate that memory cells do not necessarily derive from effector T cells and develop independently of signals from IL-2 and IL-15 by a pathway yet to be defined.

The Woodland group explains how T cell memory is induced and maintained in the respiratory tract. They point out the substantial heterogeneity among memory CD8 T cells and discuss how T cells are induced, maintained and function during antigen recall in the lung. Doherty and colleagues also explain the induction and maintenance of CD8 T cell memory in the lung. They advocate that the magnitudes of the T cell responses are a direct function of antigen dose as well as the size of the naïve and memory T cell precursor pool. The Bevan group describes mechanisms by which memory CD8 T cells are produced and maintained for extended periods. They focus on the influence of CD4 T cells and suggest these cells help maintain CD8 T cell memory by inducing cells to retain responsiveness to IL-7 and IL-15. Suhr, Sprent and colleagues deal with the issue of how homeostatic mechanisms serve to maintain stable memory populations. They explain how the cytokines IL-7 and IL-15 achieve this for CD8 T cell memory. Selin, Welsh and co-workers emphasize that in natural environments the exposure to cross-reactive agents may shape the size and reactivity patterns of long term memory T cell responses. They suggest that cross-reactive T cells (so-called heterologous immunity) may modulate the outcome of an infection for better or worse. Rocha and Tanchot take issue with nomenclature problems which plague the memory T cell field. These include inappropriate definitions, oversimplification of events, preconceived and fashionable ideas and many others. They point out that it is too soon to find unifying concepts and that memory is of necessity complex so as to deal with the highly diverse world of pathogens.

Reviews by Shen and Reiner take us into the novel (for most cellular immunologists) realm of epigenetic control and transcription factors involved in T cell memory responses. The Shen group persuades us that the enhanced functionality of memory T cells over naïve cells depends on epigenetic modifications such as DNA demethylation and histone acetylation imprinted on memory cells. Reiner and colleagues explain molecular programming of memory T cell differentiation in terms of the involvement of various transcription factors. The Restifo group reminds us (lest we forget) that CD8 T cells are important for tumor immunotherapy. Their article deals with the issue of “corrupted” and dysfunctional CD8 T cell memory and how it might be corrected to achieve immunity to cancers. This phenomenon of T cell ‘exhaustion’ is critical not only for tumors but also for chronic virus infections as discussed by Rene van Lier and Pantaleo. Rene van Lier and colleagues discuss the diversity of CD8 T cell responses to human viral infections. They relate this to the different types of virus infections emphasizing latent and chronic agents. The Pantaleo group continues with this theme and deals with the protective effects of both CD4 and CD8 human T cells. They propose that the heterogeneity in phenotype and function observed are specific to each virus and are largely influenced by the levels of antigen load. They advocate that polyfunctional T cells responses (eg. IL-2 and IFN-γ secreting) represent the most useful functional signatures for immunity to most viruses. This viewpoint is shared by many memory aficionados.

The importance of pre-existing neutralizing antibody present in circulation and at mucosal surfaces in conferring protective immunity cannot be overstated – in fact, many of our most successful vaccines work primarily (though not exclusively) by this mechanism. Several articles in this issue focus on various critical aspects of humoral immunity. The McHeyzer-Williams article discusses events that impact on the different stages of B cell development into long lived memory cells. Calame discusses the role of various transcription factors that regulate humoral responses and the generation of plasma cells. These molecular studies have provided major insight into the differentiation and maintenance of long lived plasma cells. Shlomchik and colleagues tackle the question of how the B cell immune system responds qualitatively and quantitatively to pathogen re-exposure. The advantages and disadvantages of various models to study this important question are also discussed. Radbruch and colleagues describe a mathematical model to explain the maintenance rate of old plasma cells at frequencies high enough to provide protection yet accommodate new specificities. Lanzavecchia, Sallusto and colleagues discuss their work on the maintenance of serological memory and how one can exploit the memory B cell repertoire to make human monoclonal antibodies. Zinkernagel and Hengartner highlight the importance of pre-existing neutralizing antibody and activated T cells in protection and examine the interesting relationship between immunological memory and protective immunity. They also discuss the challenges of producing protective vaccines against pathogens that cause persistent infections. Finally, Ammana, Slifka and Crotty examine how our most successful vaccine, the smallpox vaccine, works. They address the fascinating issue of how long-lived plasma cells can account for the extraordinary duration of antibody mediated immunity following smallpox immunization.

The quest to understand immunological memory has, at least, two tangible rewards; first, the joy of solving challenging problems in fundamental immunology, and second, the satisfaction of using this fundamental knowledge to benefit and improve human health. So far, the rewards have come mostly in the first category. Indeed, the majority of our best vaccines have been empirically derived. We anticipate, however, that given the rapid advances in our understanding of T and B cell memory, things are about to change. The time is not far when application of the fundamental discoveries of memory research should begin to yield dividends in the areas of vaccines and immunological interventions.